Dronabinol, a synthetic version of delta-9-tetrahydrocannabinol (delta-9-THC), is currently approved by regulatory authorities for use as an antiemetic in cancer chemotherapy as well as an appetite stimulant for patients afflicted with the AIDS virus. The product is currently marketed under the commercial name Marinol® as an oral soft gelatin capsule in which the drug substance is dissolved in sesame oil.
Dronabinol is the principal psychoactive agent in marijuana and has a number of complex effects on the central nervous system, including central sympathomimetic activity. Dronabinol also has anti-nausea/antiemetic activity. The mechanism whereby dronabinol acts to reduce nausea and emesis is not well understood, in part because the neuro-pharmacology of the vomiting center and its connections to input centers is not known in sufficient detail. Dronabinol, however, appears to act via a mechanism distinct from that of other antiemetics which function, typically, by dopaminergic antagonism, such as, phenothiazines, butyrophenones, or benzamides or that of H, antagonists, which are used most commonly for prevention of motion sickness and are included in many antiemetic regimens to suppress the extrapyramidal effects of the neuroleptic anti-dopaminergics.
Bioavailability of the current formulation ranges from 10-20% due to a high first pass metabolism associated with oral administration. The current formulation has an onset of action ranging from 0.5 to 1 hour. In addition, maximum concentrations may not be reached until several hours after oral administration.
As discussed, dronabinol is almost completely absorbed (90-95%) after single oral doses. Dronabinol has an extensive first pass hepatic metabolism and, also, high lipid solubility. As a result, only 10% to 20% of an orally administered dose will be found in systemic circulation at peak levels, the balance being sequestered in lipid tissues or having been metabolized during the first pass. Dronabinol and its principle active metabolite, 11-OH-delta-9-THC, are present in approximately equal concentrations in plasma. Concentration of both the parent drug and the metabolite peaks at approximately 2 to 4 hours after oral dosing and declines over several days. Values for clearance average are about 0.2 L/kg/hr, but are highly variable due to the complexity of cannabinoid distribution.
The elimination phase of dronabinol can be described using a two-compartment model with an initial alpha half-life of about 4 hours and a terminal beta half-life of 25 to 36 hours.
Because of its very high lipid solubility, dronabinol is sequestered in fatty tissues leading to a very large apparent volume of distribution, approximately 10 L/kg and to the creation of a depot compartment from which dronabinol is excreted at low levels for prolonged periods of time. This depot compartment produces the long beta half-life excretion phase for dronabinol. Biliary excretion is the major route of elimination with about half of the oral dose being recovered from the feces within 72 hours as contrasted with 10% to 15% recovered from urine.
The major urinary metabolite in humans following oral administration is 11-nor-9-lc carboxy-delta-9-tetrahydrocannabinol. It accounts for approximately 27% of the total THC metabolites excreted in urine. Less than 5% of an oral dose is recovered unchanged in the feces.
It would be desirable to improve bioavailabity and quicken onset of action for the above indications as well as for the treatment of alternative conditions, such as spinal cord spasticity, glaucoma, and Alzheimer's disease. Alternative routes previously suggested to overcome oral delivery limitations include the administration of drugs (including delta-9-tetrahydrocannabinol) through inhalation. It has been demonstrated in the literature, for example, that smoking marijuana cigarettes (the main constituent being dronanbinol, i.e., delta-9-THC) results in improved bioavailability (60-70%). However, there are obvious disadvantages relating to smoking marijuana, including raw material impurities, depression of alveolar macrophage activity, and bronchial irritation. Another approach suggested in initial reports at a meeting on Feb. 24, 1998, sponsored by the Institute of Medicine, National Academy of Sciences, Division of Neuroscience and Behavioral Health in Washington, D.C., was to study and use particle size data developed in a conventional nebulizer system to try to enhance bioavailability of delta-9-tetrahydrocannabinol after deep lung administration. Among the suggested routes of administration suggested by the prior art are those using aerosol formulations to be inhaled as described in Volicer, U.S. Pat. No. 5,804,592, granted Sep. 8, 1998, based on Provisional Application with a priority date of May 7, 1997. However, as presently advised, there has been no prior disclosure of experiments which used formulations comprising delta-9-tetrahydrocannabinol and semiaqueous solvents comprising judiciously selected volumetric ratios of alcohol, water and pharmaceutically acceptable glycols to enhance partitioning, and no evidence of enhanced bioavailability in warm-blooded animals, including humans, has been known for such compositions prior to the present invention. It still remains desirable, therefore, to develop a new safe, fast acting delivery system for delta-9-tetrahydrocannabinol to improve bioavailability, and such a system is the subject matter of the present invention.